Hereditary Spastic Paraplegia (HSP) comprises a group of neurodegenerative disorders characterized by progressive spasticity of the lower limbs and has fascinating clinical and pathophysiological overlap with amyotrophic lateral sclerosis (ALS), hereditary motor neuropathies, and axonal neuropathies. HSP is genetically heterogeneous with autosomal dominant, autosomal recessive, and X-linked forms. Genes have been identified for only 14 of the 30 reported HSP chromosomal loci. The identification and molecular characterization of additional HSP genes is key to improve our understanding of the underlying pathophysiology. Thus, we will strive to identify the underlying gene of the well-defined HSP locus on chromosome 19q (SPG12). We will have access to DNA samples from all known linked SPG12 families through collaborations with investigators in France (Dr Alexandra Durr), Italy (Dr. Antonio Orlacchio), and the UK (Dr. Evan Reid). An identified SPG12 gene will be included in our mutation screening and functional studies. The indispensable basis of our successful HSP genetic program has been the collection of HSP families over more than 15 years. This program has recently been moved with the principal investigators to the University of Miami. The expansion and clinical improvement of this collection is the basis of our genetic and molecular HSP research. Recently we have identified the underlying gene for the SPG31 locus, receptor expression enhancing protein 1 (REEP1), which appears to represent 6.5% of all HSP patients making it the third most common HSP gene after spastin and atlastin. We will clinically study the REEP1 families in more detail and screen for additional REEP1 mutations in a sample of 370 HSP patients collected by Dr. de Jonghe, University of Antwerp. Finally, we propose the molecular characterization of the mutations identified in the novel mitochondrial protein REEP1 and possibly in the SPG12 gene. Dr. Moraes is a world-renowned specialist for mitochondrial disease mechanisms and is a new investigator on this grant specifically to address the third aim. We strongly believe that only such an integrated approach - clinical, genetic, and molecular/functional - will yield significant progress in the understanding of HSP.